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| | <StructureSection load='6zz1' size='340' side='right'caption='[[6zz1]], [[Resolution|resolution]] 1.64Å' scene=''> | | <StructureSection load='6zz1' size='340' side='right'caption='[[6zz1]], [[Resolution|resolution]] 1.64Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6zz1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZZ1 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZZ1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6zz1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZZ1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZZ1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QOK:7-(2-methoxyethoxymethyl)-1,3-dimethyl-purine-2,6-dione'>QOK</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.64Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6zvo|6zvo]], [[6zle|6zle]], [[6zpr|6zpr]]</div></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QOK:7-(2-methoxyethoxymethyl)-1,3-dimethyl-purine-2,6-dione'>QOK</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zz1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zz1 OCA], [http://pdbe.org/6zz1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zz1 RCSB], [http://www.ebi.ac.uk/pdbsum/6zz1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zz1 ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6zz1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zz1 OCA], [https://pdbe.org/6zz1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zz1 RCSB], [https://www.ebi.ac.uk/pdbsum/6zz1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zz1 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MLKL_HUMAN MLKL_HUMAN]] Required for the execution of programmed necrosis.<ref>PMID:22265414</ref> | + | [https://www.uniprot.org/uniprot/MLKL_HUMAN MLKL_HUMAN] Required for the execution of programmed necrosis.<ref>PMID:22265414</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bauer, M]] | + | [[Category: Bauer M]] |
| - | [[Category: Fiegen, D]] | + | [[Category: Fiegen D]] |
| - | [[Category: Nar, H]] | + | [[Category: Nar H]] |
| - | [[Category: Lipid binding protein]]
| + | |
| - | [[Category: Necroptosis]]
| + | |
| Structural highlights
Function
MLKL_HUMAN Required for the execution of programmed necrosis.[1]
Publication Abstract from PubMed
As an alternative pathway of controlled cell death, necroptosis can be triggered by tumor necrosis factor via the kinases RIPK1/RIPK3 and the effector protein mixed-lineage kinase domain-like protein (MLKL). Upon activation, MLKL oligomerizes and integrates into the plasma membrane via its executioner domain. Here, we present the X-ray and NMR costructures of the human MLKL executioner domain covalently bound via Cys86 to a xanthine class inhibitor. The structures reveal that the compound stabilizes the interaction between the auto-inhibitory brace helix alpha6 and the four-helix bundle by stacking to Phe148. An NMR-based functional assay observing the conformation of this helix showed that the F148A mutant is unresponsive to the compound, providing further evidence for the importance of this interaction. Real-time and diffusion NMR studies demonstrate that xanthine derivatives inhibit MLKL oligomerization. Finally, we show that the other well-known MLKL inhibitor Necrosulfonamide, which also covalently modifies Cys86, must employ a different mode of action.
Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis.,Rubbelke M, Fiegen D, Bauer M, Binder F, Hamilton J, King J, Thamm S, Nar H, Zeeb M Proc Natl Acad Sci U S A. 2020 Dec 14. pii: 2017406117. doi:, 10.1073/pnas.2017406117. PMID:33318170[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wang Z, Jiang H, Chen S, Du F, Wang X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell. 2012 Jan 20;148(1-2):228-43. doi: 10.1016/j.cell.2011.11.030. PMID:22265414 doi:http://dx.doi.org/10.1016/j.cell.2011.11.030
- ↑ Rubbelke M, Fiegen D, Bauer M, Binder F, Hamilton J, King J, Thamm S, Nar H, Zeeb M. Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis. Proc Natl Acad Sci U S A. 2020 Dec 14. pii: 2017406117. doi:, 10.1073/pnas.2017406117. PMID:33318170 doi:http://dx.doi.org/10.1073/pnas.2017406117
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